(1) Retinoic acid markedly reduced the level of intracellular fibronectin in a time-and concentration- dependent fashion in NIH-3T3 cells, but not in H-ras transfected cells. Pulse- chase experiments indicated that retinoic acid affects the rate of fibronectin biosynthesis rather than its turnover. The retinoid did not change the steady-state levels of fibronectin transcripts, suggesting an action at the translational level. Similar effects were also observed in other fibroblast cells. Retinoic acid (RA) also caused a marked downmodulation of the levels of RARalpha protein. The RA-dependent downmodulation of fibronectin biosynthesis is mediated by the retinoic acid receptors' RARs, whereas RXRs are involved in the observed downmodulation of the RARalpha by RA. Moreover, the block of RA-responsiveness in ras-transformed cells could not be overcome by the overexpression of RARalpha. These studies have defined fibronectin and RARalpha as targets of RA in fibroblast cells and have shown that H-ras transformation renders the cells resistant to RA action. (2) The effect of retinoic acid on the growth of cultured tumorigenic human and rodent cells was assessed in serum-free media. Of the 15 cell lines tested, 9 were growth inhibited (RA-sensitive), whereas 6 were unaffected (resistant). A relationship between ability to metabolize RA and inhibition of cell growth was discovered. (3) Dietary pharmacological retinoic acid specifically inhibited malignant conversion in the two-stage system of skin carcinogenesis, using 12-O-tetradecanoylphorbol-13-acetate as the tumor promoter, but was active against both tumor promotion and malignant conversion in mezerein-promoted female SENCAR mice.